Tumorigenesis involves sequential genetic lesions in pathways that regulate fundamental biological processes such as cell proliferation and cell survival (Hahn & Weinberg (2002) Nat. Rev. Cancer 2:331-41; Vogelstein & Kinzler (2004) Nat. Med. 10:789-99). It has been suggested that both the p16Ink4a-CycD/Cdk4-pRb and Arf-MDM2/MDMX-p53 pathways must be inactivated during tumorigenesis (Vogelstein & Kinzler (2004) supra).
The primary role of the Rb pathway is to regulate cell proliferation (Sherr & McCormick (2002) Cancer Cell 2:103-112; Chau & Wang (2003) Nat. Rev. Cancer 3:130-8), and that of the p53 pathway is to regulate responses to cellular insults such as DNA damage or oncogenic stress (Vogelstein, et al. (2000) Nature 408:307-10; Oren (2003) Cell Death Differ. 10 431-42; Prives & Hall (1999) J. Pathol. 187:112-26). The Rb and p53 pathways may be inactivated by mutations in the RB1 and p53 tumor suppressor genes themselves or through genetic alterations of genes encoding modulators and/or effectors in these pathways.
For example, some cancers have MDM2 gene amplifications that functionally suppress the p53 pathway by reducing the steady-state levels of the p53 protein (Honda, et al. (1997) FEBS Lett. 420:25-7; Kubbutat, et al. (1997) Nature 387:299-303; Momand, et al. (1998) Nucl. Acids Res. 26:3453-9). When MDM2-mediated destabilization of p53 is blocked by the inhibitor nutlin-3 in tumors with MDM2 gene amplifications, the p53 pathway is restored, and tumor cells undergo p53-mediated cell cycle arrest, cell death, or both (Yang, et al. (2005) Cancer Cell 7:547-59; Vassilev, et al. (2004) Science 303:844-8). Therefore, identification of genetic perturbations in the Rb and p53 pathways can provide specific targets for chemotherapy.
Genetic evidence has shown that when a p53 mutation is the tumor-initiating event, subsequent genetic lesions such as loss of the p16INK4A gene disrupt the Rb pathway (Guran, et al. (1999) Cancer Genet. Cytogenet. 113:145-51; Rogan, et al. (1995) Mol. Cell. Biol. 15:4745-53). However, retinoblastomas that arise from cells that have lost RB1 have not been found to contain subsequent genetic lesions in the p53 gene (Kato, et al. (1996) Cancer Lett. 106:75-82) or pathway (Nork, et al. (1997) Arch Ophthalmol. 115:213-219). Recent genetic studies in Rb; p107-deficient mouse retinae have extended these findings and led to the proposal that retinoblastoma is a unique tumor that bypasses the p53 pathway because the cell of origin is intrinsically death resistant (Dyer & Bremner (2005) Nat. Rev. Cancer 5:91-101).
It has been suggested that inactivation of the Rb pathway is sufficient for retinoblastoma formation because the Arf-MDM2/MDMX-p53 oncogenic stress response pathway is never activated (Dyer & Bremner (2005) supra). This has important implications for cancer genetics and treatment. It suggests that depending on the cell-of-origin, cancer can proceed down a “fast track” of tumorigenesis, because the cells are intrinsically programmed to bypass certain tumor suppressor pathways (Dyer & Bremner (2005) supra). Thus, therapeutic targets may differ depending on the initiating genetic lesion and the pathways bypassed.
Each year, approximately 250 to 300 cases of retinoblastoma are diagnosed in the United States and 5,000 cases are diagnosed worldwide (Shields, C. L. and J. A. Shields. 2004. Cancer Control 11:317-327). The primary goals of therapy are cure and ocular salvage; however, enucleation remains a frequent treatment for advanced intraocular disease. In developing countries, patients more often present with advanced disease and the long-term survival rate is approximately 50% (Rodriguez-Galindo et al. 2008. Pediatrics 122:763-770). The most widely used chemotherapy treatment regimen for retinoblastoma includes systemic administration of etoposide (ETO), carboplatin (CBP) and vincristin (VCR) and for early stage disease it is possible to eliminate ETO without affecting outcomes (Rodriguez-Galindo et al. 2003. J. Clin. Oncol. 21:2019-2025). Ongoing clinical trials are focused on incorporating systemic topotecan (TPT) into the currently used treatment regimens.
The eye provides a unique opportunity for local, concentrated delivery of specific chemotherapeutic drugs in order to minimizes systemic exposure and side effects. Previously, both CBP (Abramson et al. 1999. Ophthalmology 106:1947-1950) and topotecan (TPT; Chantada et al. 2009. Invest. Opthalmol. Vis. Sci. 50:1492-1496) have been tested in retinoblastoma patients using subconjunctival delivery. A recent preclinical study compared the efficacy and toxicity of the combination of subconjunctival TPT (TPTsubconj) with systemic CBP to subconjunctival CBP (CBPsubconj) with systemic TPT (Nemeth et al. 2011. Cancer 117:421-434). The latter combination had the best efficacy and least toxicity in preclinical models. However, the local, periocular inflammation associated with CBPsubconj may limit its widespread use in children with retinoblastoma.